Current CV markers, LDL-C, LDL-P, and total cholesterol, are not able to identify coronary artery disease (CAD) patients or subjects that have an elevated risk for CV events, such as AMI, ACS, stroke and CV death, from patients having more stable disease.
The term myocardial infarction pathologically denotes the death of cardiac myocytes due to extended ischemia, which may be caused by an increase in perfusion demand or a decrease in blood flow. The event is called “acute” if it is sudden and serious. Diagnosis of AMI is determined by a high clinical suspicion from history and physical examination, in addition to changes in cardiac biomarkers (creatinine kinase MB [CK-MB], troponins, and myoglobin) and electrocardiogram (ECG) findings. Imaging techniques, such as two-dimensional echocardiography, are also useful in demonstrating myocardial dysfunction. Current CV markers, LDL-C, LDL-P, and total cholesterol, fail to predict the likelihood of the cardiovascular disease (CVD) event occurring.
Acute coronary syndrome (ACS) is a term used for any condition brought on by sudden, reduced blood flow to the heart. The first sign of acute coronary syndrome can be sudden stopping of the heart called cardiac arrest. Acute coronary syndrome is often diagnosed in an emergency room or hospital with the same cardiac biomarkers or electrocardiogram (ECG) as AMI, that provide evidence on damaged heart tissue or problems in the heart's electric activity.
A stroke is the loss of brain function due to a disturbance in the blood supply to the brain, depriving brain tissue of oxygen and food. Within minutes, brain cells begin to die. A stroke may be caused by a blocked artery (ischemic stroke) or a leaking or burst blood vessel (hemorrhagic stroke). Some people may experience a temporary disruption of blood flow through their brain (transient ischemic attack, or TIA). Strokes are usually diagnosed by brain imaging and carrying out physical tests.
Sudden cardiac death (SCD) is a sudden, unexpected death caused by loss of heart function, also named as sudden cardiac arrest (SCA). Sudden cardiac arrest is not a heart attack (myocardial infarction). Heart attacks occur when there is a blockage in one or more of the coronary arteries, preventing the heart from receiving enough oxygen-rich blood. In contrast, sudden cardiac arrest occurs when the electrical system to the heart malfunctions and suddenly becomes very irregular. The heart beats dangerously fast. Ventricular fibrillation may occur, and blood is not delivered to the body. In the first few minutes, the greatest concern is that blood flow to the brain will be reduced so drastically that a person will lose consciousness. Death follows unless emergency treatment is begun immediately. Sudden cardiac arrest happens without warning and is rarely diagnosed with medical tests as its happening. Instead, SCA often is diagnosed after it happens, by ruling out other causes of a person's sudden collapse.
AMI, ACS, stroke and sudden cardiac death are diagnosed in acute stage, but predictive markers are not available. The risk factors behind these events are for example, age, hypolipidemia, hypertension, smoking, diabetes, CAD or previous heart attack. Yet, no diagnostic test that could predict the events exists, and cardiovascular diseases are the leading cause of death worldwide. Furthermore, the costs to society that are associated with CVD are higher than for any other group of diseases. The same tests that are used for diagnosing CVD are utilized in predicting the events. Today the most innovative approach is to use LDL-C, LDL-P, HDL-C, Lp(a), Lp-PLA2 or CRP. However, none of the listed lipid based markers (LDL-C, LDL-P, Lp(a), Lp-PLA2) provide clinically useful predictive information allowing stratification to aid physicians. CRP has been promising in the research setting, however it has proven to be unspecific (CRP is an acute phase reactant that can react to many different stimuli leading to highly variable test results) and thus CRP values are difficult to interpret in the clinical use. There is an unmet need for a diagnostic test that could predict CV events, such as AMI (acute myocardial infarction), ACS (acute coronary syndrome), stroke and CV death.
Ischemia is a restriction in blood supply to tissues. When blood flow to the heart is reduced, the heart does not receive enough oxygen and nutrients, and the condition is called myocardial ischemia or cardiac ischemia. Myocardial ischemia can damage the heart muscle leading, e.g., to a heart attack. Therefore, an early detection of ischemia is crucial for survival of patients. There is an unmet need for diagnostic markers that could identify patients with early stage acute ischemia that can be either symptomatic or asymptomatic (silent ischemia).
The ceramide and lysophospholipid (LPL) based risk stratification offers improved performance compared to any other lipid based biomarker today.
Alterations in specific LPLs, i.e. lysophosphatidylcholines (LPCs), have been observed in primary prevention settings related to CAD (BG Medicine disclosures EP2293077 and U.S. Pat. No. 8,321,154 as well as Fernandez et al., Plos one, 2013, 8(8):e71846). However, these studies have not provided information regarding the outcome of the patients, and therefore do not report those markers that could be used to identify CAD patients at high risk for future outcome events. Moreover, these studies did not investigate the association of ceramides related to CAD and did not investigate LPLs other than LPCs.
A large group of lipid molecules, including certain ceramides and LPCs, and ratios calculated from two lipid molecules have been identified for predicting CV outcomes in CAD patients who are undergoing statin treatment or who are not undergoing statin treatment or for identifying high-risk CAD patients or predicting whether a subject is at risk for developing CV events. However, there remains a desire for improved methods of predicting the risk of a patient developing a CV event, such as AMI, ACS, stroke, and CV death.
The current application recognizes value of both ceramides (Tarasov et al: J Clin Endocrinol Metab., 2014, 99(1):E45-52) and lysophospholipids (Goncalves et al., Arterioscler Thromb Vasc Biol. 2012 June; 32(6):1505-12 PMID:22499993) in development of CVD. It has earlier been reported that blood ceramide levels can be lowered by certain lipid lowering compounds including statin drugs (Tarasov et al., J Clin Endocrinol Metab., 2014, 99(1):E45-52) and newly developed Lp-PLA2 inhibitors may potentially affect Lp-PLA2 mediated hydrolysis of low-density lipoprotein-oxidized phospholipids leading to generation of LPLs. Therefore, Cer/LPL-ratio can provide significant clinical improvement compared for instance to certain previously disclosed Cer/Cer-ratios as Cer/LPL-ratios can offer a better monitoring opportunity for the drug treatment effects; Cer can be affected by statin type of cholesterol lowering compounds, while LPL component may be controlled by drugs affecting for instance Lp-PLA2 activity.
This application provides new ceramide and LPL markers with superior AUC, sensitivity and specificity. This superior performance could not have been predicted from art known biomarkers.